Mycobacterium tuberculosis remains a global public health problem. The natural history of tuberculosis (TB) can vary widely among individuals; while most patients have sub-clinical, latent infection, a subpopulation of individuals infected with M. tuberculosis progress to primary disease or reactivation TB. A rigorous comparison of susceptible and resistant individuals would be useful to study mechanisms of pathogenesis, but controlled infections of humans is not possible. The goal of this exploratory (R21) proposal is to establish the basic framework needed to identify host defense genes associated with different TB disease states by gene expression profiling. We will exploit a non-human primate (NHP) model of TB as a system to evaluate host defenses. Using high density DNA microarrays, we will measure gene expression in lung tissue of normal macaques and of infected macaques that exhibit two distinct disease states: active disease and latent infection. We hypothesize differential patterns of gene expression will be responsible for pathologic manifestations (granuloma versus non-granulomatous infection) and clinical conditions (active versus latent). This information will increase our understanding of host defenses and pathogenesis of M. tuberculosis. Our specific aims include: Aim 1: To determine the regional variability among grossly comparable lung tissue from the same animal, thereby evaluating the homogeneity of gene expression profiles. This will provide critical information on sampling bias and what is necessary to characterize an individual's response. Aim 2: To resolve some complexity of gene expression measured in M. tuberculosis-infected animals using known expression profiles. This will test the contributions of specific cell types and signaling pathways to the overall gene expression profile. Aim 3: To identify patterns of gene expression that distinguish between animals with active disease and latent infection. This will compare active and latent infection in an attempt to identify factors important in susceptibility to particular disease states. This work described in this application will establish a process to evaluate host defenses in the NHP model; a process that will be applicable to multiple future studies. Ultimately, representative genes will be evaluated for their role in immunity and host defenses, and as markers of vulnerability to clinical disease. [unreadable] [unreadable]